1. Field of the Invention
The present invention relates to compounds and methods for modulating alcohol consumption, alcohol dependence and/or alcohol abuse.
2. Description of the Related Art
Excessive alcohol consumption, alcohol dependence and alcohol abuse are among the most serious drug problems of Western societies. In the United States, it is estimated that up to 10% of the population abuse alcohol. The economic cost to the nation is estimated at more than $185 billion per year. Excessive alcohol consumption also brings with it social and psychological damages such as children born with fetal alcohol syndrome, alcohol related accidents, marital disharmony, spousal or child abuse, and the like. Accordingly, safe and effective treatments for limiting and/or preventing alcohol consumption are needed.
Success in the development of pharmacotherapies for addictive disorders, including nicotine and opioid addiction, and a more widespread recognition that alcohol dependence and abuse is a medical rather than moral problem have harnessed growing support in the search for and development of pharmaceutical agents for this medical condition. However, as alcoholism is a complex disease promoted by a wide range of factors, it has been difficult to develop effective modulators of alcohol consumption.
The compound daidzin has been shown to selectively suppress ethanol intake in ethanol-preferring Syrian golden hamsters as well as in other ethanol-drinking animal models such as rats (Keung et al. (1993) Proc. Natl. Acad. Sci. USA 90:10008; Keung et al (1994) EXS 71:371; Overstreet et al. (1996) Alcohol. Clin. Exp. Res. 20:659; Lin et al. (1996) Alcohol. Clin. Exp. Res. 20:1083-1087). However, daidzin administered orally does not affect hamster ethanol intake.
Daidzin inhibits the conversion of monoamines such as serotonin (5-HT) and dopamine (DA) into their respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4, -dihydrozyphenylacetic acid (DOPAC), in isolated hamster and rat liver mitochondria (Keung et al. (1998) Proc. Natl. Acad. Sci. USA 95:2198). Recent data indicates that the antidipsotropic activity of daidzin is not mediated by the monoamines but rather by their respective metabolic aldehyde intermediates, 5-hydroxyindoleacetaldehyde (5-HIAL) and/or 3,4-dihydroxyphenylacetaldehyde (DOPAL), which accumulate in the presence of daidzin.
Several recent patents and a pending patent application address the use of daidzin and daidzin analogs useful for the inhibition of aldehyde dehydrogenase and/or alcohol consumption. U.S. Pat. Nos. 5,204,369, 5,624,910 and 5,885,028 disclose methods of inhibiting the mitochondrial aldehyde dehydrogenase (ALDH-2) or treating alcohol consumption using daidzin and specific daidzin analogs. U.S. Pat. No. 6,121,010 discloses screening assays used to identify compounds for reducing alcohol consumption. U.S. Pat. No. 6,255,497 provides compounds which are daidzin analogs. U.S. Utility application Ser. No. 09/616,718 is directed to methods for inhibiting ALDH-2 and reducing alcohol consumption in a human using daidzin analogs. Each issued patent and patent application is incorporated herein by reference in its entirety.
Despite the development of compounds such as daidzin and daidzin analogs, there remains a need to develop antidipsotropic compounds having improved efficacy and enhanced pharmacological properties.